INHIBITORY EFFECTS OF LOW-MOLECULAR-WEIGHT HEPARIN ON MEDIATOR RELEASE BY MAST-CELLS - PREFERENTIAL INHIBITION OF CYTOKINE PRODUCTION AND MAST-CELL DEPENDENT CUTANEOUS INFLAMMATION

There has been substantial evidence that suggests that heparin may mod ulate various aspects of immune function and inflammation in addition to its well known anticoagulant activity. In this regard heparin was f ound to suppress cell-mediated immune responses or asthmatic reactions to allergen challenge. In the present study we analyse the effects of low molecular weight heparin (LMWH) on mast cell degranulation and cy tokine production in vitro and on the elicitation of IgE-mediated mast cell-dependent late cutaneous allergic inflammation in vivo. We have established that LMWH preferentially inhibited tumour necrosis factor- alpha (TNF-alpha) and IL-4 production without having any significant e ffect on mast cell degranulation. These effects have been observed in mast cells derived from three different origins that were activated by either immunological or non-immunological stimuli. We have shown that there is inhibition of TNF-alpha production (and not neutralization o f activity), as elimination of the drug after a short preincubation an d addition of LMWH to rTNF-alpha had no effect on TNF-alpha-mediated c ytotoxic activity. These results were also confirmed by ELISA. In vivo , s.c. injection of the LMWH inhibited the leucocyte infiltration asso ciated with the late cutaneous response which followed passive cutaneo us anaphylaxis (PCA) reaction, without affecting mast cell numbers or degranulation. These data suggest that LMWH may have an inhibitory rol e in mast cell-mediated allergic inflammation, and thus might be consi dered as a possible therapeutic modality.